Methods and apparatus for dispensing medicaments into a punctal plug

ABSTRACT

This invention discloses methods and apparatus for providing a dispensing a material with an active agent into an ophthalmic device. Some embodiments include dispensing high viscous materials into a punctal plug.

FIELD OF USE

This invention describes methods and apparatus for dispensing one or more materials, such as a medicament, into a punctal plug reservoir and, more specifically, in some embodiments, dispensing a drug component including excipients into a cavity of a punctal plug.

BACKGROUND

Medicaments frequently are administered to the eye for the treatment of ocular diseases and disorders. Conventional means for delivering medicaments to the eye involve topical application to the surface of the eye. The eye is uniquely suited to topical administration because, when properly constituted, topically applied medicaments can penetrate through the cornea and rise to therapeutic concentration levels inside the eye. Medicaments for ocular diseases and disorders may be administered orally or by injection, but such administration routes are disadvantageous in that, in oral administration, the active agent may reach the eye in too low a concentration to have the desired pharmacological effect and their use is complicated by significant, systemic side effects and injections pose the risk of infection.

The majority of ocular medicaments are currently delivered topically using eye drops which, though effective for some applications, are inefficient. When a drop of liquid is added to the eye, it overfills the conjunctival sac, the pocket between the eye and the lids, causing a substantial portion of the drop to be lost due to overflow of the lid margin onto the cheek. In addition, a substantial portion of the drop that remains on the ocular surface is drained into the lacrimal puncta, diluting the concentration of the drug.

Accordingly, alternative methods and devices for delivering medicaments to an ophthalmic area may be beneficial.

SUMMARY

The present invention relates to devices for administering a medicament via a punctal plug, and includes methods and apparatus for deposition of a medicament in a punctal plug cavity wherein the medicament can subsequently be delivered to a patient with the punctal plug inserted into a punctum.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a punctal plug and method for deposition into a punctal plug according to some embodiments of the present invention.

FIG. 2A illustrates apparatus for punctal plug deposition according to some embodiments of the present invention.

FIG. 3 illustrates additional aspects of apparatus for punctal plug deposition according to some embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes apparatus and methods for forming punctal plugs that may be used to deliver active agents to one or both of the nasolacrimal duct and to the tear fluid of the eye. In some embodiments, a location for dissemination of an active agent is positioned to release the active agent into tear fluid and preferably with minimal release into the nasolacrimal duct. Some embodiments include apparatus and methods for forming a punctal plug comprising, consisting essentially of, and consisting of: a punctal plug body having a first end and a second end; a surface extending between the two ends; a reservoir contained within the punctal plug body wherein the reservoir comprises, consists essentially of and consists of an active agent-containing material and an active agent, wherein the active agent is present in a continuous or discontinuous concentration gradient within the active agent-containing material. The punctal plug may additionally comprise a defined area, such as an opening in the punctal plug, which is more conducive to elution or other dissemination of the active agent from the punctal plug cavity to an area proximate to the punctal plug. Some preferred embodiments include an area conducive to dissemination of the active agent comprising an opening with a diameter which is smaller than a diameter of the cavity containing the active ingredient.

The present invention additionally provides devices, and methods for their use and manufacture, that can be used to deliver active agents into a cavity in a punctal plug in a controlled manner.

It has been known to fill a cavity in a punctal plug via insertion of a rod, or other rigid or semi rigid article. The rod can include a pharmaceutical or other medicament. However, the physical conditions of a punctum may include physical manipulation and the presence of moisture. Insertion of a rod of medicament into a plug can be difficult.

Definitions:

As used herein, the term “active agent” refers to an agent capable of treating, inhibiting, or preventing a disorder or a disease. Exemplary active agents include, without limitation, pharmaceuticals and nutraceuticals. Preferred active agents are capable of treating, inhibiting, or preventing a disorder or a disease of one or more of the eye, nose and throat.

As used herein, the term “punctal plug” refers to a device of a size and shape suitable for insertion into the inferior or superior lacrimal canaliculus of the eye through, respectively, the inferior or superior lacrimal punctum.

As used herein, the term “opening” refers to an opening in the punctal plug body of a device of the invention of a size and shape through which the active agent can pass. Preferably, only the active agent can pass through the opening. The opening may be covered with a membrane, mesh, grid or it may be uncovered. The membrane, mesh, or grid may be one or more of porous, semi-porous, permeable, semi-permeable, and biodegradable.

Referring now to FIG. 1, at 1A a punctal plug device 101 is illustrated with an opening 102 which fluidly communicates with a cavity 105 formed in the punctal plug body. At 1B, a dispenser tip 103 is positioned proximate to the opening 102 and dispenses a material 104 through the opening 102 and into the cavity 105. At 1C, the cavity 105 is shown filled by the dispenser tip 103 with a material 104 containing an active agent. Examples of active agents can include one or more of: bimatoprost; bimatoprost with an ethyleneoxynalacetate (“EVA”) membrane in amounts greater than 0 and less than 25%.

In various embodiments of the present invention, the material 104 containing one or more active agents-and an active agent therein is deposited in the cavity 105 of a punctal plug device in small doses and at high viscosity. For example, in some embodiments, the material 104 can have a viscosity of between 1 (one) centipoise to over 1,000,000 (one million) centipoise. In addition, some embodiments include deposition of small doses of the material 104, such as between 10 (ten) picoliters and 10,000 (ten thousand) picoliters. The material 104 may also include one or more excipients. The excipients may be the portion of the material 104 which provides the high viscous properties.

The cavity may be any size and/or shape that a punctal plug design may support. In some embodiments, the volume of the cavity 105 will be about between 10 and 100 nanoliters. Some specific embodiments include a cavity volume of about between 40 nanoliters and 50 nanoliters. An opening 102 to a cavity into which a dispenser tip may be inserted, may be, for example, include a diameter of between about 0.1 mm to 0.4 mm and a cavity 105 may include a depth of between about 0.5 mm to about 2.0 mm. In some preferred embodiments, the opening 102 will be about 0.2 mm and the depth of the cavity will be about 1.5 mm. Additional preferred aspects of embodiments can include a design with a 0.385 diameter and 1.5 mm length with a cavity volume of 175 nL.

The active agent may be dispersed throughout the active agent-containing material 104 or dissolved within the material 104. Alternatively, the active agent may be contained in inclusions, particulates, droplets, or micro-encapsulated within the material 104. Still as another alternative, the active agent may be covalently bonded to the material 104 and released by hydrolysis, enzymatic degradation and the like. Yet as another alternative, the active agent may be in a reservoir within the material 104.

According to some embodiments of the present invention the active agent may be released from the punctal plug device 101 in a controlled manner, meaning over a period of time by using an active agent-containing material 104 in which the agent is present in a continuous concentration gradient throughout the material 104 or by using a discontinuous concentration gradient. Additional embodiments include a device that exhibits a “burst” or immediate release upon insertion of an amount of active agent that is greater than the average release rate over time.

Referring now to FIG. 2, an example of some embodiments of the present invention which include a punctal plug active agent pump 200 for depositing the material with an active ingredient 104 into a cavity 105 of a punctal plug device 101 (illustrated in FIG. 1). Generally, the pump 200 includes a reservoir, such as a cartridge 201, mounted in a pump body 207 and attached to provide fluid communication to a dispenser tip 203. The cartridge 201 can include, for example, a removable syringe.

The cartridge 201 can be formed from a polycarbonate, stainless steel or other rigid or semi-rigid material. In some preferred embodiments, the cartridge is formed from a material that can be sterilized and also withstand heating during the deposition process. Additionally, in some embodiments, the cartridge 201 will have an end proximate to the dispenser tip 203 and an end distal to the dispenser tip, wherein the end proximate to the dispenser tip can include a lure lock mechanism for securing the cartridge 201 to a dispenser body 202. Other locking or fastening mechanisms may also be used to secured the cartridge 201 in a position proximate to and in fluid communication with the dispenser tip 203. Some embodiments may therefore include designs of a polycarbonate or stainless steel syringe.

Some embodiments can include a “smart pump” such as a positive pressure pump with a computer controlled needle valve, which control starts and stops and material flow for a range of viscosities. A computer controlled needle valve provides active valving to control flow characteristics, such as, for example: opening, closing and suck-back associated with the pumping of the active agent-containing material 104. A dead volume inside the pump can range in some embodiments from between about 0.025 cc to 0.3 cc. Such degrees of control, allow the present invention to dispense very small volumes of an active agent-containing material 104. Some embodiments can include dispensing volumes of 50 picoliters or less and in some preferred embodiments, volumes of between 20 picoliters to 60 picoliters. In another aspect, a range of viscosities of an active agent-containing material 104 from 1 centipoise to over 1,000,000 centipoise. Other embodiments include a range of viscosities of between 500,000 centipoise to 3,500,000 centipoise. One exemplary pump mechanism can include a high pressure positive displacement pump, such as those offered for commercial use by nScript, Inc.

Some preferred embodiments will include one or more heating sources 204-206 for heating the material with an active ingredient 104 while it is in one or more of: a) the cartridge 201; b) the dispenser body 202; and c) the dispenser tip 203. The heat source can include, for example, one or more of: electrically resistive elements; thermoelectric devices and heated fluid paths. As illustrated, in some embodiments, a heating source 205 may be located along side the cartridge 201 and allow the material with an active ingredient 104 to be kept at an elevated temperature while in the cartridge 201. Some embodiments can also include a heater element 204 in or proximate to the pump body 207. Some embodiments may also include temperature requirements that may be adjusted according to material properties excipients to be deposited.

In another aspect, some embodiments of the present invention include a temperature probe 206. The temperature probe can include a transducer for providing a digital or analog output indicating a temperature of a designated portion of the punctal plug active agent pump 200. Embodiments can include an electronic feedback circuit (not shown), which allows control of an amount of heat applied to the active ingredient 104. In some embodiments, the feedback constitutes a closed loop feedback design.

Additionally, in some embodiments, an amount of heat applied to the material containing an active ingredient 104 can be used to control a viscosity of the material containing an active ingredient 104. Typically, a higher amount of heat applied will lower the viscosity of the material containing an active ingredient 104 and allow for less pressure to be applied to move the material containing an active ingredient 104 through the punctal plug active agent pump 200. By way of example, a material containing an active ingredient 104 can be dispensed through the dispenser tip 203 at a temperature of between 40° C. and 80° C. and in some preferred embodiments at a temperature of between 60° C. and 70° C. In some particular embodiments, a punctal plug 101 into which the material containing the active material 104 is dispensed is also heated to a temperature of between 40° C. and 80° C. In some embodiments, the application of heat to the punctal plug 101 can provide additionally elasticity to the plug during the deposition allowing the cavity 105 to expand and more easily accept the material containing an active ingredient 104. In various embodiments, a preferred temperature may be based upon one or more of: an active ingredient used; an excipient included in the material containing an active ingredient 104; and

Referring now to FIG. 3, a perspective view illustrates a pump 200 with a dispenser tip 301 and a quick change tip base 302. The quick change tip base facilitates removal/replacement of a tip by an operator. As illustrated in FIG. 3, in some embodiments, pump body 304 can be mounted on a track 304, or other mechanical or robotic device which allows motion in one, two or three dimensions. The motion may be controlled in some embodiments, motion is controlled via automation and allows for the alignment of the dispenser tip 301 with a punctal plug (not illustrated in FIG. 3). In still another aspect, some embodiments may include a automated vision system to facilitate automated alignment and filling of plugs.

Without being bound to any particular theory, it is believed that an active agent-containing material 104 that does not undergo significant chemical degradation during the time desired for the release of active agent will release the agent by diffusion through the matrix to a device's release surfaces, meaning surfaces of the active agent-containing material 104 in contact with a person's body fluid. According to Fick's Law, the diffusive transport or flux, J, of the agent through the active agent-containing material 104 is governed at each point and each time by the local concentration gradient, the diffusivity of the active agent with the material D, and the spatial variation of the cross-sectional geometry of the device.

Some exemplary embodiments can include a material with a mix of excipients and active agents. Pre-mixing apparatus and processes may include twin-screw compounding, chaotic mixing, solvent mixing, or spray drying, or other mixing mechanisms. An exemplary compound can include: 25% bimatoprost as an active agent; 37.5% ethylene vinyl acetate, EVA as a first excipient and 37.5% polycaprolactone, PCL as a second excipient.

The pre-mixed material can be loaded into the heated or non-heated syringe 200 as pellets. Pellets are not a requirement; the material 104 can be in the form of one or more of: a powder, fluff and other mediums. Additionally, in some embodiments, such as those in which it is desired to avoid multiple thermal cycle exposure of an active agent and/or to minimize air bubbles, the heated syringe may be directly attached to the micro-compounder so that the pre-mixed material is directly supplied into a nano-dosing dispensing system, such as those described above, without having to cool it to room temperature or lower. As such, in some embodiments the material containing an active agent may be supplied to the nano-dispensing system in a melt form.

In another aspect of the present invention, a local gradient of a concentration of active agent may be controlled by placing more active agent at one location in the material containing an active agent 104 relative to another location. Alternatively, the matrix may be have a gradient, meaning that one section of the material 104 has a first concentration and the concentration abruptly changes to a second, different concentration in an adjacent section of the matrix. The diffusivity for the active agent may also be spatially controlled by varying one or more of the chemical composition, porosity, and crystallinity of the active agent-containing material 104.

Additionally, the spatial variation of the material's cross-sectional geometry may be used to control diffusivity. For example, if the material 104 was in the form of a straight rod that has a uniform active agent concentration, diffusivity will be reduced when the area at the open end of the material 104 is significantly smaller than the average of the entire material 104. Preferably, the material 104 area at the open end of the device is no more than one-half of the average cross sectional area of the material, meaning the cross section determined perpendicular to the primary dimension of active agent transport use.

One of ordinary skill in the art will recognize that, depending on how one varies one or more of the local concentration gradient, the diffusivity of the active agent from the material D, and the spatial variation of the cross-sectional geometry of the device, a variety of release profiles may be obtained including, without limitation first order, second order, biphasic, pulsatile and the like. For example, either or both of the active agent concentration and diffusivity may increase from the surface to the center of the active agent-containing material in order to achieve more initial release. Alternatively, either or both may be increased or decreased and then increased again within the material to achieve a pulsatile release profile. The ability to achieve a variety of release profiles by varying local concentration gradient, the diffusivity of the active agent, and the spatial variation of the cross-sectional geometry may eliminate the need for rate-limiting membranes in the device.

Devices formed according to the present invention may contain a reservoir or cavity 104 within the punctal plug body, and the cavity 104 has at least at least one active agent-containing material deposited therein. In some embodiments, the punctal plug body is preferably impermeable to the active agent, meaning only an insubstantial amount of active agent can pass there through, and the punctal plug body has at least one opening through which the active agent is released. The opening may have a membrane or permeable material covering through which the active agent may pass in therapeutic amounts.

The active agent-containing material useful in the devices of the invention is any material that is capable of containing the active agent, does not alter the chemical characteristics of the active agent, and does not significantly chemically degrade or physically dissolve when placed in contact with ocular fluids. Preferably, the active agent-containing material is non-biodegradable, meaning that it does not degrade to a substantial degree upon exposure to biologically active substances typically present in mammals. Additionally, the active agent-containing material is capable of releasing the active agent by one or more of diffusion, degradation, or hydrolyzation. Preferably, the active agent-containing material is a polymeric material, meaning that it is a material made of one or more types of polymers.

When the active agent-containing material is combined with the active agent, the material may also contain one or more materials that are insoluble in water and non-biodegradable, but from which the active agent can diffuse. For example, if the active agent-containing material is a polymeric material, the material may be composed of one or more polymers that are insoluble in water and non-biodegradable.

Suitable polymeric materials for the active agent-containing material include, without limitation, hydrophobic and hydrophilic absorbable and non-absorbable polymers. Suitable hydrophobic, non-absorbable polymers include, without limitation, ethylene vinyl alcohol (“EVA”), fluorinated polymers including without limitation, polytetrafluoroethylene (“PTFE”) and polyvinylidene fluoride (“PVDF”), polypropylene, polyethylene, polyisobutylene, nylon, polyurethanes, polyacrylates and methacrylates, polyvinyl palmitate, polyvinyl stearates, polyvinyl myristate, cyanoacrylates, epoxies, silicones, copolymers thereof with hydrophobic or hydrophilic monomers, and blends thereof with hydrophilic or hydrophobic polymers and excipients.

Hydrophilic, non-absorbable polymers useful in the invention include, without limitation, cross-linked poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(vinyl alcohol), poly(hydroxyethyl acrylate or methacrylate), poly(vinylpyrrolidone), polyacrylic acid, poly(ethyloxazoline), and poly(dimethyl acrylamide), copolymers thereof with hydrophobic or hydrophilic monomers, and blends thereof with hydrophilic or hydrophobic polymers and excipients.

Hydrophobic, absorbable polymers that may be used include, without limitation, aliphatic polyesters, polyesters derived from fatty acids, poly(amino acids), poly(ether-esters), poly(ester amides), polyalkylene oxalates, polyamides, poly(iminocarbonates), polycarbonates, polyorthoesteres, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, phosphoesters, poly)anhydrides), polypropylene fumarates, polyphosphazenes, and blends thereof. Examples of useful hydrophilic, absorbable polymers include, without limitation, polysaccharides and carbohydrates including, without limitation, crosslinked alginate, hyaluronic acid, dextran, pectin, hydroxyethyl cellulose, hydroxy propyl cellulose, gellan gum, guar gum, keratin sulfate, chondroitin sulfate, dermatan sulfate, proteins including, without limitation, collagen, gelatin, fibrin, albumin and ovalbumin, and phospholipids including, without limitation, phosphoryl choline derivatives and polysulfobetains.

More preferably, the active agent-containing material is a polymeric material that is polycaprolactone. Still more preferably, the material is poly(epsilon-caprolactone), and ethylene vinyl acetate of molecular weights between about 10,000 and 80,0000. About 0 to about 100 weight percent polycaprolactone and about 100 to about 0 weight percent of the ethylene vinyl acetate are used based on the total weight of the polymeric material and, preferably, about 50% each of polycaprolactone and ethylene vinyl acetate is used.

The polymeric material used is preferably greater than about 99% pure and the active agents are preferably greater than about 97% pure. One of ordinary skill in the art will recognize that in compounding, the conditions under which compounding is carried out will need to take into account the characteristics of the active agent to ensure that the active agents do not become degraded by the process. The polycaprolactone and ethylene vinyl acetate preferably are combined with the desired active agent or agents, micro-compounded, and then extruded.

In a preferred embodiment, the active agent-containing material is a polymeric material that is combined with at least one active agent to form a highly viscous material, such as, for example with a viscosity of between 500,000 cP and 4,000,000 cP. Preferably the viscosity of the active agent containing material can be decreased by heating the active agent containing material while it is contained in, or passing through a dispensing pump according to the present invention.

Conclusion

The present invention, as described above and as further defined by the claims below, provides methods of processing punctal plugs and apparatus for implementing such methods, as well as punctal plugs formed thereby. 

1. An apparatus for forming an ophthalmic device, the apparatus comprising: a mount for receiving the ophthalmic device, wherein the ophthalmic device comprises a cavity for containing an active agent-containing material; a nozzle through which the excipient and the active agent are dispensed into the cavity of the ophthalmic device; and a pump for dispensing the excipient through the nozzle into the cavity of the ophthalmic device.
 2. The apparatus of claim 1, wherein the device is a punctal plug.
 3. The apparatus of claim 2, wherein the active agent-containing material comprises poly(epsilon-caprolactone) and ethylene vinyl acetate.
 4. The apparatus of claim 3, wherein the poly(epsilon-caprolactone) and ethylene vinyl acetate are each present in an amount of about 50 weight percent.
 5. The apparatus of claim 1 or 3, wherein the active agent-containing material comprises one or more fiber or fiber-like structures.
 6. The apparatus of claim 1 or 2, wherein the device further comprises a release modulating component selected from the group consisting of biodegradable semi-permeable membranes, non-biodegradable semi-permeable membranes, pores and combinations thereof.
 7. The apparatus of claims 1 or 2, wherein the active-agent containing material further comprises an outer segment comprising a first material having a low concentration of the active agent and an inner segment comprising a second material having a high concentration of the active agent, wherein the permeability of the first material to the active agent is less than the permeability of the second material.
 8. The apparatus of claim 2 wherein the active agent-containing material further comprises one or more of a phase separated inclusion, a destabilizing inclusion or a stabilizing inclusion.
 9. The apparatus of claim 2 wherein the pump comprises a positive displacement pump.
 10. The apparatus of claim 2 wherein the punctal plug comprises a body having a first end and a second end; a surface extending between the two ends; a reservoir contained within the body wherein the reservoir comprises at least one opening, an active agent-containing material and an active agent, wherein the active agent is present in a continuous or discontinuous concentration gradient within the active agent-containing material.
 11. The apparatus of claim 2 additionally comprising a reservoir for containing a volume of the active agent-containing material to be dispensed.
 12. The apparatus of claim 11 wherein the reservoir comprises a syringe cartridge.
 13. The apparatus of claim 12 wherein the syringe comprises polycarbonate.
 14. The apparatus of claim 11, additionally comprising a heater device positioned to heat a volume of active agent-containing material contained within the reservoir.
 15. The apparatus of claim 2 additionally comprising a heater device positioned to heat an active agent-containing material in the nozzle.
 16. The apparatus of claim 2 wherein the pump for dispensing the active agent-containing material through the nozzle into the cavity of the punctal plug is capable of dispensing a volume of material of 50 picoliters of less.
 17. The apparatus of claim 2 wherein the pump for dispensing the active agent-containing material through the nozzle into the cavity of the punctal plug is capable of dispensing a volume of material with a viscosity comprising between 1 centipoise to 1,000,000 centipoise.
 18. The apparatus of claim 2 wherein the pump for dispensing the active agent-containing material through the nozzle into the cavity of the punctal plug is capable of dispensing a volume of material with a viscosity comprising between 500,000 centipoise to 3,500,000 centipoise. 